Hypopituitarism : clinical assessment in different conditions Kokshoorn, N.E.

Kokshoorn, N.E.

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Kokshoorn, N. E. (2011, December 7). Hypopituitarism : clinical assessment in different conditions. Retrieved from https://hdl.handle.net/1887/18194

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Chapter 2

Clinical review: Hypopituitarism following traumatic brain injury – the prevalence is aff ected by the use of diff erent dynamic tests and diff erent normal values

Nieke E. Kokshoorn, Moniek J.E. Wassenaar, Nienke R. Biermasz, Ferdinand Roelfsema, Johannes W.A. Smit, Johannes A. Romijn and Alberto M. Pereira

Eur J Endocrinol. 2010 Jan;162(1): 11–18

38

Abstract

Objective: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. Th ese can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism.

Methods: Systematic review of studies reporting prevalence of hypopituitarism in adults ≥ 1 year aft er TBI focusing on used (dynamic) tests and biochemical criteria.

Results: We included data from 14 studies with a total of 931 patients.

Th ere was considerable variation in defi nition of hypopituitarism.

Overall, reported prevalences of severe GH defi ciency varied between 2 and 39%. Prevalences were 8–20% using the GHRH-arginine test (cut- off < 9 μg/L), 11–39% using the glucagon test (cut-off 1–5 μg/L), 2% using the GHRH test (no cut-off ) and 15–18% using the insulin tolerance test (ITT) (cut-off < 3 μg/L).

Overall, the reported prevalence of secondary adrenal insuffi ciency had a broad range from 0 to 60%. Th is prevalence was 0–60% with basal cortisol (cut-off < 220 or < 440 nmol/L), 7–19% using the ACTH test and 5% with the ITT as fi rst test (cut-off < 500 or < 550 nmol/L).

Secondary hypothyroidism was present in 0–19% (free T ₄ ) or 5–15%

(TRH stimulation). Secondary hypogonadism was present in 0–29%.

Conclusion: Th e reported variations in the prevalence rates of hypopituitarism aft er TBI are in part caused by diff erences in defi nitions, endocrine assessments of hypopituitarism and confounding factors.

Th ese methodological issues prohibit simple generalizations of results of

original studies on TBI-associated hypopituitarism in the perspective of

meta-analyses or reviews.

39

Introduction

In recent years, an increasing number of studies have reported the presence of pituitary insuffi ciency in patients who experienced traumatic brain injury (TBI) (1–14). Th e prevalence of pituitary insuffi ciency aft er TBI appeared to be unexpectedly high (15;16). Remarkably, the prevalence rates varied considerably among the diff erent studies, ranging from 15 to even 90% of the patients.

Several factors infl uence the prevalence of hypopituitarism aft er TBI. First, the time interval between TBI and the assessment of pituitary function, since hormone alterations mimicking pituitary insuffi ciency are prevalent in the early post-traumatic period. Second, the type and severity of the brain injury aff ects the prevalence of hypopituitarism, because persistent pituitary insuffi ciency is only frequent aft er severe TBI (7;15). Th ird, endocrine tests, assays, and criteria for the diagnosis of hypopituitarism diff er between the studies. Although many reviews have addressed TBI-related hypopituitarism, a detailed comparison of these methodological issues between the diff erent studies has not been performed for each pituitary axis.

We hypothesized that these methodological diff erences may have

contributed, at least in part, to the discrepancies in prevalence rates of

hypopituitarism aft er TBI, reported by the diff erent studies. Th erefore,

the aim of this study was to critically compare the pituitary function

tests, and defi nitions of hypopituitarism between studies that assessed

the long term outcome of TBI on pituitary function.

40

Patients and methods

Search strategy

We performed a search in PubMed, EMBASE, Web of Science, and the Cochrane database, for all published studies on the association between TBI and hypopituitarism. Th e following search strategy was used:

(Traumatic Brain Injury OR Traumatic brain injuries) AND (traumatic OR trauma) AND (Hypopituitarism OR Hypopituitar* OR Hypothalamus Hypophysis System OR “Hypothalamopituitary dysfunction” OR “pituitary dysfunction” OR Hypothalamo-Hypophyseal System OR Pituitary Gland OR Hypophysis).

In addition, the references of relevant articles were checked for additional articles. Th e search was performed on 23 March 2009. Only original articles were included. We used the following exclusion criteria:

pediatric or adolescent population, publications concerning pituitary testing < 12 months aft er injury (a median of 12 months was accepted), and articles that evaluated pituitary insuffi ciency aft er subarachnoidal bleeding (SAB).

Data review

Th e following data were extracted from each study: 1) age and gender, 2) the endocrine tests used for assessment of each pituitary axis, 3)  defi nitions used for pituitary insuffi ciency for each pituitary axis, 4) hormone assays, 5) reference values provided in the manuscript, and 6) use of control populations. Tables were constructed per pituitary axis.

Th ese tables are added as supplemental data fi les. Th e growth hormone

(GH)-IGF-I axis (Table 2), the pituitary-adrenal axis (Table 3), the

pituitary-thyroidal axis (Table 4), the pituitary-gonadal axis (Table 5),

and prolactin (Table 6).

41

Results

We identifi ed 278 articles, of which 218 were excluded on the basis of

title and abstract. Of the remaining 60 articles, 46 were reviews. Finally,

14  original studies were included with a total of 931 patients. Details

of these studies are summarized in Table 1. Th e number of patients

evaluated by the diff erent studies varied between 22 and 105.

42

T a b le 1 . S tu d ie s o n T B I a n d p it u it a ry d e fi ci e n c y S tudy Y ear of public a tion N o . of pa tien ts T ime of t esting p ost TBI [mon ths (median)]

T rauma se v erit y (GCS) BMI (k g/m

)

A n y pituitar y defi cienc y (%) Kelly et al .(6) 2000 22 3–276 (median 26) 3–15 25.1±6.5 37 Lieber man et al .(9) 2001 70 1–276 (median 13) 3–15 84% GCS ≤ 8 NR 69 B ondanelli et al .(3) 2004 50 12–64 3–15 54% GCS ≤ 8 24.6±0.4 54 A gha et al .(1) 2004 102 6–36 (median 17) 3–13 56% GCS ≤ 8 NR 28 P opo vic et al .(10) 2004 67 12–264 3–13 24.8±0.5 34 A imar etti et al .(2) 2005 70 12 3–15 21% GCS ≤ 8 23.8±0.4 23 Leal- C er ro et al .(8) 2005 99 >12 ≤ 8 25.2±3.0 (n=44) 25 S chneider et al .(11) 2006 70 12 3–15 23.8±3.2 36 Tanr iv er di et al .(12) 2006 52 12 3–15 25% GCS ≤ 8 NR 51 Her rmann et al .(5) 2006 76 5–47 ≤ 8 25.8±4.2 24 Bushnik et al .(4) 2007 64 > 12 mon ths NR NR 90 K lose et al .(7) 2007 104 10–27 (median 13) 3–15 38% GCS ≤ 8 25* (17–39) 15 Tanr iv er di et al .(14) 2008 30 36 3–15 16.7% GCS ≤ 8 NR 30 W ach ter et al .(13) 2009 55 NR 3–15 17% GCS ≤ 8 NR 25 Total No . of pa tien ts: 931 B M I, b o d y m a ss in d e x re p o rt e d a s th e m e a n ± S E M ; G C S , G la sg o w C o m a S ca le so re ; T B I, tr a u m a ti c b ra in in ju ry ; N R , n o t re p o rt e d . * re p o rt e d a s m e d ia n (r a n g e )

43 The GH-IGF-I axis

Th e prevalence of GH defi ciency (GHD) ranged between 2 and 66%

(severe GHD 39%; Figures 1 and 2 and Suppl Table 2). Th e presence of GHD was associated with higher body mass index (BMI) values in some of the studies (Figure 1). In addition to basal serum GH and IGF-I values, all studies used a dynamic test to assess GH secretory reserve. However, diff erent dynamic tests were used.

Th ree studies (196/931=21% of all patients) used the combined GHRH- arginine test as the fi rst screening. Th e criterion for severe GHD was a peak GH level < 9.0 μg/L in all three, which was not adjusted for BMI.

Prevalence rates of severe GHD varied between 8 and 20% (weighted mean 12%) (2;3;5). Schneider et  al. (11) also used the GHRH-arginine test, but only in a subset of the patients (those with abnormal serum cortisol levels, n=32); the prevalence of GHD in this study was 10%.

Two studies (112/931=12% of all patients) used an insulin tolerance test (ITT) as the primary screening test (6;7). Th e criterion for severe GHD was a peak GH response < 3 μg/L in both, and the prevalence of GHD was comparable (18 and 15% respectively; weighted mean 16%).

Of the eight remaining studies, three used a stimulation test with glucagon (n=209) (1;4;9) with prevalence rates for severe GHD between 11 and 39% (weighted mean 20%). Th e cut-off values diff ered considerably and varied between 1 and 5 µg/L between these studies. Just one study used a stimulation test with GHRH only (number of patients not recorded) reporting a GHD prevalence of 2% (13). Two studies (n=119) used the combined GHRH-GHRP6 test with a prevalence of 15 and 33%

respectively (weighted mean 21%) (10;12). Th e cut-off values were similar (GH < 10 μg/L) within these studies, and were derived from another report (17).

Finally, two studies used a combination of these tests (8;14). For

instance, Agha et al. (1) used a glucagon stimulation test for the initial

screening in 102 subjects, and in case of incomplete GH response, they

used an ITT (n=14) or combined GHRH plus arginine test (n=4) to

confi rm GHD.

44

= GHD = N o GHD 3 2

3 6 * *

* 2 4

2 8

n=7 n=10

* 2 0

n=41 n=91n=70 n=88

n=23

n=16 n=420

Body mas s in de x ( BM I) (k

2

g/m

) 0 W eigh ted a h to ta l mea n (± 9 5 % C I)

n=47

n=17 n=6

n=7n=84

b c d e f g

n=34

n=11 n=10 n=26

F ig u re 1 . B o d y m a ss in d e x in p a ti e n ts d ia g n o se d w it h v e rs u s th o se w it h o u t G H d e fi ci e n c y (d a ta a v a il a b le o n ly in 8 o u t o f th e 1 6 st u d ie s) . a , L ie b e rm a n et  a l.  9 ); b , A g h a et a l.( 1) ; c , P o p o v ic et a l. (1 0 ); d , L e a l- C e rr o et a l. (8 ); e , T a n ri v e rd i e t a l.( 12 ); f, H e rr m a n n et a l.( 5 ); g , K lo se et a l.( 7 ); h , T a n ri v e rd i e t a l.( 1 4 ); i, w e ig h te d to ta l m e a n (m e a n ± 9 5 % C I: n o G H D 2 4 .5 (2 4 .2 –2 4 .9 ) v e rs u s G H D 2 7. 7 (2 6 .7 –2 8 .8 ) k g /m

). G H D , G H d e fi ci e n c y ; B M I, b o d y m a ss in d e x ; * P < 0 .0 5 .

D a ta re p o rt e d a s m e d ia n w it h r a n g e ; n o t i n cl u d e d i n t h e t o ta l w e ig h te d m e a n .

45

GHRH-arginine as initial test

15 20 25

GHRH-arginine as confirmation test n=70

A

15 20

25 ITT as initial test

Weighted

*

**

B

Weighted mean 13%

0 5 10 15

Bondanelli Aimaretti Herrmann Schneider

n=50 n=76

n=32

0 5 10 15

Kelly Klose n=22

n=104

mean 16%

P re v a le n ce s e v e re G H D ( % ) P re v a le n ce s e v e re G H D ( % )

25 30 35

n=32

GHRH-GHRP6 as initial test C

35 40 45

n=59

Glucagon stimulation test as initial test

**

D

5 10 15 20 25

n=67

Weighted mean 21%

5 10 15 20 25 30

n=102

n=70

Weighted mean 21%

* *

P re v a le n ce s e v e re G H D (%) P re v a le n ce s e v e re G H D (%)

0

Popovic et al.

Tanriverdi et al.

0 Agha

et al.

Bushnik et al.

Lieberman et al.

E Combination of tests

25 Δ Δ

5 10 15 20

GHRH test

n=99

n=30

Δ

Pr e v al e n ce s e v e re G H D ( % )

0 Leal-Cerro et al.

Tanriverdi et al.

Wachter et al.

P n=55

et al. et al. et al. et al. et al. et al.

Figure 2. Absolute and weighted mean prevalence rates of severe GH defi ciency (GHD) according to the stimulation tests used per study. The number of patients tested is depicted in each bar. Panel A: the combined GHRH-arginine test; defi nition severe GHD:

peak GH < 9 μg/L for all four studies. Panel B: the insulin tolerance test (ITT); *defi nition severe GHD: GH < 95%

CL according to AUC; **defi nition severe GHD: peak GH < 3 μg/L. Panel C: the combined GHRH-GHRP6 test; defi nition severe GHD: peak GH < 10 μg/L for both studies. Panel D: the glucagon stimulation test;

defi nition severe GHD: *peak GH < 3 μg/L; **peak GH

< 5 μg/L. Panel E: combined stimulation tests as initial

screening followed by confi rmation test; ΔGHRH-

GHRP6 test as initial test; ITT and glucagon stimulation

test as confi rmation tests; ΔΔGHRH-GHRP6 test as initial

test; glucagon stimulation test as confi rmation test.

46

The Pituitary-Adrenal axis

Th e prevalence of secondary adrenal insuffi ciency defi ciency ranged from 0 to 60% between the studies (Figure 3, Suppl Table 3).

Four studies (251/931=27% of all patients) only measured basal morning fasting serum cortisol and/or ACTH levels (2–4;10), resulting in prevalence rates between 0 and 60% (weighted mean 15%). Th e criteria for pituitary-adrenal insuffi ciency diff ered between three studies (cortisol < 220–440 nmol/L), and were not reported in the fourth study (10). Th e study reporting the highest prevalence of 60% used a cut-off value of 440 nmol/L (4).

Four studies (145/931=12% of all patients) used an ACTH stimulation test (Synacthen; either with 1 or 250 μg). However, only one study performed this test in all patients and the prevalence of ACTH defi ciency was 7% (9). In the other three studies, only a subset of the patients (those with subnormal basal cortisol levels) underwent stimulation with ACTH.

Th e prevalence in these studies varied between 7 and 19% (weighted mean 10%) (11;12;14).

One study (55/931=6% of all patients) used nonstimulated cortisol values between 1600 and 2000 h (reference values 63–339 nmol/L), which was followed by a corticotrope releasing hormone (CRH) test only in those with values below this reference range, or in those who responded confi rmatory to a specifi c questionnaire (13).

In the remaining fi ve studies (403/931=43% of all patients), the ITT

was used in 169 patients as a primary test (n=112) resulting in a prevalence

of 5% in both studies (6;7), or as a confi rmation test in a subset of the

patients. Two studies measured basal serum cortisol levels and used ITT

as a confi rmation test (prevalence of 3 and 11% respectively) (5;8). One

study assessed primarily with a glucagon stimulation test (n=102), and

used the ITT and ACTH tests to confi rm ACTH defi ciency (prevalence

13%) (1). Th e criteria for a normal cortisol response to hypoglycemia

were a peak cortisol level > 550 nmol/L in one (8), and > 500 nmol/L

in three other studies (1;5;7). Th e fi ft h study used a control group of

18 healthy subjects to defi ne normal cortisol responses to ITT (cortisol

response < 95% confi dence limit according to the obtained area under

the curve)  (6). Th e CRH test was used in only one study and did not

report the number of patients (13).

47

50 60 70

Basal serum ACTH and cortisol levels

n=64

***

A

16 18 20

ACTH test in total population

n=52

ACTH test in subset of population

**

B

10 20 30 40 50

P re v a le n ce A C T H d e fi ci e n cy ( % )

Weighted mean 15%

* ** ** 4

6 8 10 12 14

P re v a le n ce A C T H d e fi ci e nc y ( % )

Weighted mean 10%

n=70

n=70

n=30

*

*

**

Bondanelli et al.

0

Popovic et al.

Aimaretti et al.

Bushnik et al.

n=50 n=67 n=70

0 2

Lieberman et al.

Schneider et al.

Tanriverdi et al.

Tanriverdi et al.

C

12 ITT as initial test ITT as confirmation test

14 Other tests D

6 8 10 12

e ACTH defi ci e nc y (%)

Weighted

* **

***

n=99

6 8 10 12 14

e A CT H d e fi ci e n cy ( % )

n=102

Δ

0 2 4

Kelly et al.

Klose et al.

Leal-Cerro et al.

Herrmann et al.

P re v a le n ce mean 5%

n=22

**

n=76

0 2 4

Agha et al.

Wachter et al.

P re v a le n ce

n=55 ΔΔ

Figure 3. Absolute and weighted mean prevalence rates of corticotropin (HPA axis) defi ciency according to the stimulation test used per study. The number of patients tested is depicted in each bar. Panel A: basal cortisol concentrations only using diff erent cut-off levels; *cut-off level: NR; **cut- off level: cortisol < 220 nmol/L; ***cut-off level: cortisol < 440 nmol/L. Panel B: the ACTH stimulation test *using 250 µg ACTH and peak cortisol < 500 nmol/L; **using 1 µg ACTH and peak cortisol

< 550   mol/L. Panel C: the insulin tolerance test (ITT); *peak cortisol < 95% CL according to AUC;

**peak cortisol < 500 nmol/L; ***peak cortisol < 550 nmol/L. Panel D: other stimulation tests: Δthe

glucagon stimulation test; ΔΔCRH test.NR, not reported.

48

The Hypothalamus-Pituitary-Thyroid axis

Th e prevalence of hypothalamus-pituitary-thyroid axis defi ciency ranged from 0 to 19% between the studies (Suppl Table 4).

Th e criteria for TSH defi ciency were diff erent. Nine studies used basal free thyroxine (fT ₄ ) and TSH levels only. Within these studies, the cut-off value for decreased fT ₄ varied between 8 and 12 pmol/L (2;5;7;11;14;18;19). In two studies, reference values were not reported (4;10), one of which (Bushnik et al.) reported the highest prevalence of secondary hypothyroidism.

Th e thyroid-releasing hormone (TRH) stimulation test was used in fi ve studies, using i.v. doses of 200 (13) and 500 µg (5;6;8;9). Th e criterion for a normal response diff ered considerably: a TSH peak response

> 7 mIU/L, a TSH peak between 5 and 30 mIU/L, or were not reported (12;13).

Th e prevalence rates between the studies that only measured basal fT ₄ levels varied between 0 and 19% (weighted mean 5%) (1–5;7;10;11;14), and between 5 and 15% (weighted mean 8%) in those that also used TRH (6;8;9;12;13).

The Hypothalamus-Pituitary-Gonadal axis

Th e hypothalamus-pituitary-gonadal axis defi ciency ranged from 0 to 29% (weighted mean 13%) between the studies (Table 5). Basal LH and FSH were measured in all but one study (4). Basal estradiol (E ₂ in women) was measured in 9 studies, and the menstrual history was recorded in 10 out of 14 studies. Testosterone (in men) was measured in all studies. In four studies, a GnRH stimulation test was performed in a subset of the patients (6;8;9;13). Th e criterion for a normal test response diff ered between the studies (Suppl Table 5). Th e defi nition of secondary hypogonadism was mainly based on basal testosterone (in men) and E ₂ concentrations (in women) below the reference ranges, in the presence of decreased or normal LH and FSH levels. A subset of the studies also incorporated the GnRH test result (see above) and menstrual cycle abnormalities in premenopausal females.

Prolactin

Th e prevalence of abnormal serum PRL concentrations ranged from

0 to 16% (Suppl Table 6). Abnormal PRL secretion was defi ned as

hyperprolactinemia (8/14 studies) (1;2;5;7;9;11;12;14), hypoprolactinemia

49

(one study) (6), or both (3). In accordance, prevalence rates were between

3 and 12% using the defi nition of hyperprolactinemia, 0% using the

defi nition of hypoprolactinemia, and 16% using the combination of

both. Out of the 14 studies, 10 measured basal serum PRL concentrations

only (1–3;5;7;9–12;14). Th ree studies also used a TRH test (doses 100 and

500 μg respectively) (6;8;13). Prevalence rates were not reported in two of

these (8;13) and were 0% in the third (6).

50

Discussion

Th is review demonstrates that the endocrine evaluations and defi nitions of hypopituitarism diff er considerably among the studies that have assessed TBI-related hypopituitarism. From the existing literature, the notion emerges that most of the tests that are currently used to establish the diagnosis of hypopituitarism in general, and GHD in specifi c, are not validated suffi ciently regarding cut-off values, reproducibility, and dependence on confounding factors in TBI patients.

In general, there are hardly any data on reproducibility of tests or dependence on confounding factors in TBI patients. One factor that comes forward in the current review is the potential eff ect of increased BMI, which in general is associated with decreased GH responses to GH stimulation tests. Th erefore, increased BMI may result in an inadvertently higher incidence rate of GHD, if the cut-off values for normal GH responses to GH stimulation tests are not adapted according to BMI. All these methodological issues limit the applicability of the individual studies, i.e. the decision whether the study results are valid for patients to whom the results are generalizable but who are subjected to a diff erent endocrine diagnostic assessment than the original study population. Moreover, these methodological limitations prohibit simple generalizations of the results from the perspective of a meta-analysis or a review.

Th e question arises whether post-traumatic hypopituitarism,

especially GHD, has been overdiagnosed on the basis of the older

cross-sectional studies. Consensus guidelines for the evaluation of

adult GHD state that diff erent dynamic tests can be used to diagnose

GHD, including the ITT, the glucagon stimulation test, the combined

GHRH-arginine test, and the combined GHRH-GHRP6 test (20). Th e

present assessment, however, documents a higher prevalence of GHD

for the glucagon stimulation test and the combined GHRH-GHRP6

test, compared to the results of the combined GHRH-arginine test and

the ITT. With the exception of the ITT (which was used in only 12%

51

of the patients (6;7)), the outcome of each test varied greatly (Figure 2) using diff erent (glucagon stimulation test) or similar cut-off levels (other test). In addition, the studies that used two dynamic tests to assess GH reserve revealed a lower prevalence of GHD than the studies with only one test. Moreover, the results of GH stimulation tests are confounded by BMI, with higher BMI being associated with decreased GH responses.

Although BMI-adjusted reference values have been reported (21), none of the studies on TBI-associated GHD reports adjusted their cut-off values for BMI. Moreover, the data indicate that BMI tends to be higher in the TBI patients with GHD (Figure 1). Finally, an important aspect is that most patients had only GHD or one additional pituitary hormone defi ciency. Th erefore, one test may not be suffi ciently reliable and the use of two tests would increase the confi dence in the diagnosis, although only if the two tests yield concordant results. However, the application of two tests may introduce an even greater uncertainty in case of discordant results. Th is discrepancy has been documented for instance in GHD in irradiated patients, in whom the attenuation in GH responses to the ITT was greater compared with the combined GHRH-arginine test (22).

Th ese factors impose major problems for an accurate assessment of GHD in these patients. Th erefore, these methodological issues have contributed to the suspicion that GHD is probably over diagnosed in the older cross- sectional studies.

We observed similar variations in test results of the pituitary-adrenal axis (Figure 3). Th e use of diff erent tests with diff erent cut-off values resulted in prevalence rates that varied between 5 and 19%. ACTH defi ciency can be diagnosed by measuring basal early morning cortisol levels: values below 100 nmol/L are indicative of ACTH defi ciency, whereas cortisol values above 500 nmol/L essentially exclude ACTH defi ciency. Th e ACTH stimulation test is reliable in diagnosing clinically signifi cant adrenal insuffi ciency in patients who are at risk (23–25).

ACTH stimulation tests, however, are not fully reliable in excluding

the presence of mild secondary adrenal insuffi ciency (26). Th e ITT still

remains the golden standard, and has the advantage that ACTH/cortisol

and GH secretory reserve can be assessed simultaneously. If an ITT is

contraindicated, a CRH test can be alternatively used (27). Th e eff ect

of the initial choice for a specifi c stimulation test on the variation in

outcome of adrenal insuffi ciency and GHD based on the available data

aft er TBI is illustrated in Figure 4.

52

Pati ents suspec ted for p itu ita ry in su ffi ci e n cy af te r TBI Dynamic t es t ot her t hen IT T as init ial screening: 12 s tu dies (n = 8 1 9 )

ITT as initial screening: two stud ies (n = 1 1 2 ) P re v a le n ce se v e re G H D : 1 5 -1 8 % GHRH-arginine fo u r st u d ie s (n = 2 2 8 )

AC T H t e st fo u r st u d ie s (n = 1 4 5 )

P re v a le n ce H P A d e fi ci e n cy : 5% G H R H -G H R P 6 th re e s tu d ie s (n = 2 4 8 )

G S T th re e s tu d ie s (n = 2 0 9 ) P re v a le n ce H P A d e fi ci e n cy : 7 -1 9 %

P re v a le n ce se v e re G H D: 8 -2 0 %

P re v a le n ce se v e re G H D: 1 0 -3 3 %

P re v a le n ce se v e re G H D: 11-39% F ig u re 4 . E x a m p le i ll u st ra ti n g t h e e ff e c t o f i n it ia l t e st c h o ic e o n t h e v a ri a ti o n i n o u tc o m e o f p re v a le n ce r a te s o f s e v e re G H D a n d H P A a x is i n su ffi c ie n c y.

53

Th e diagnosis of secondary hypothyroidism is usually made based on fT ₄ values. However, basal fT ₄ levels show a relatively small intra- individual variability, although inter-individual variability is large (28).

As a consequence, a diagnosis of possible secondary hypothyroidism may not be straightforward, since fT ₄ levels within the normal reference range can refl ect hypothyroidism in one patient but euthyroidism in another patient. Basal TSH levels are also of limited help for the diagnosis of secondary hypothyrodism, since normal or even increased levels of TSH can be found (29). In addition, a TRH test is of limited value because patients with central hypothyroidism may show diff erent patterns of TSH responses to TRH, with absent or exaggerated responses, which considerably overlap with those found in healthy volunteers.

Moreover, the magnitude of the TSH peak is proportional to the injected TRH dose, is higher in women, and tends to decline with age (30). In accordance, the prevalence rates were not aff ected by the use of TRH stimulation. In analogy, the interpretation of the GnRH test is complex, and individual responses vary greatly in both adults and children (31).

In men, it is suffi cient to measure non-stimulated LH, FSH, and testosterone concentrations. In premenopausal women, the evaluation of the menstrual cycle is a prerequisite, whereas in postmenopausal women, the absence of increased LH and FSH levels almost invariably indicates hypogonadotropic hypogonadism.

Analytical factors will most likely also have aff ected the diff erent outcomes of the studies. For instance, the GH and cortisol assays varied between studies, and it is known that the between-laboratory performance of the GH assay is not very good. Moreover, most were not validated suffi ciently regarding normal cut-off values, reproducibility, and dependence on confounding factors even in a ‘normal’ population.

None of these tests have been validated in TBI patients at all.

Th e time point of evaluation may also infl uence outcome; therefore,

we focused only on studies in the chronic phase aft er TBI, i.e. one year

aft er the trauma. Studies that analyzed patients with a median duration

of 12 months aft er TBI, however, were also included. Th us, part of these

patients was assessed within 12 months aft er TBI. In general, the transient

eff ects of TBI mimicking pituitary insuffi ciency are almost exclusively

reported only within the fi rst six months aft er TBI (15). Th erefore, it is

unlikely that the pituitary results of the studies with a median duration

of follow-up of 12 months of TBI are caused by the transient eff ects of

54

TBI. Th is is supported by similar results of additional analyses of the remaining studies, which included only patients with a follow-up of more than 12 months aft er TBI. Lastly, the underlying mechanisms of TBI-related hypopituitarism have not been resolved. It is unclear to that extent hypothalamic versus pituitary damage is present in TBI patients with hypopituitarism and what impact these processes may have on endocrine tests.

Recently, many clinical reviews have summarized the studies on pituitary insuffi ciency aft er TBI (15;16). Th ese studies concluded that hypopituitarism is a common complication of TBI and might contribute to morbidity and poor recovery aft er brain injury (16). However, these reviews did not take into account the variability in diagnostic strategies and defi nitions of pituitary insuffi ciency. Th ese discrepancies, in addition to diff erences in inclusion and exclusion criteria, limit the possibility to compare the results of studies on TBI. We agree with Klose and Feldt- Rasmussen that future studies should be designed to ensure a high diagnostic robustness for proper identifi cation of reliable predictors, as the results may be highly dependent on diagnostic pitfalls (15).

In conclusion, the reported prevalence rates of pituitary insuffi ciency

aft er TBI vary considerably, which is associated with major diff erences

in endocrine and analytical methods of assessment and defi nitions

used for hypopituitarism. Th is does not only apply to the case of TBI-

related hypopituitarism, but most likely also to hypopituitarism caused

by pituitary diseases. Th e same caution with respect to the evaluation of

pituitary function should be considered in pituitary diseases, because the

diagnosis of defi nitive hypopituitarism remains a challenge in clinical

endocrinology. In pituitary pathology, defi nitive data on robust accuracy

of basal or dynamic hormonal tests are incomplete.

55

Su pp le m en ta l d at a T a b le 2 . G H -I G F -I A x is S tudy

N o . of pa tien ts

B asal ser um GH

B asal ser um IGF-I IT T

GHRH- ar ginine test

O ther dynamic test

C rit erion GH defi cienc y A ssa y s GH / IGF-I

O ut come (%) GH IGF -I Kelly et al . (6) 22 + + + (n=22)

– – GH < 95% CL ac cor ding t o A UC

16–24 yr : 182–780 µg/L 25–39 yr : 114–492 µg/L 40–54 yr : 90–360 µg/L

IF A/RIA* 18

Lieber man et al .(9) 70 + + – – +

(GST ; n=48)

P eak GH < 3 µg/L NR IRM A/RIA* 15 B ondanelli et al . (3) 50 + + – + (n=50)

– P eak GH < 16.5 µg/L S ev er e GHD = GH < 9 µg/L P ar tial GHD = GH 9–16.5 µg/L 20–30 yr : 135–485 µg/L 31–40 yr : 120–397 µg/L 41–50 yr : 113–306 µg/L 51–60 yr : 100–250µg/L >60 yr : 92–229 µg/L

IRM A/RIA P ar tial:28 S ev er e:8 A gha et al . (1) 102

+ + + (n=14)

+ (n=4)

+

(GST ; n=102)

GST : peak GH < 5 µg/L IT T : peak GH < 5 µg/L GHRH-ar g: peak GH < 9 µg/L IGF-I SDS: ln(IGF-I) – [5.9 –(0.0146xage in yrs)]/0.272

IRM A/ IRM A 11

56

S tudy

N o . of pa tien ts

B asal ser um GH

B asal ser um IGF-I IT T

GHRH- ar ginine test

O ther dynamic test

C rit erion GH defi cienc y A ssa y s GH / IGF-I

O ut come (%) GH IGF -I P opo vic et al .(10) 67 + + – – + (GHRH- GHRP6; n=67)

S ev er e GHD = peak GH < 10.0 μg/L GHI = peak GH < 10.0–20.0 µg/L Nor mal lev els ma tched for age and se x 11–35 nmol/L

IRM A/ RIA P ar tial: 30 S ev er e: 15 A imar etti et al .(2) 70 + + – + (n=70)

– P eak GH < 16.5 µg/L S ev er e GHD = peak GH < 9.0 µg/L 25

c en tile age -r ela ted nor mal limits IRM A/RIA P ar tial: 39 S ev er e: 20 Leal- C er ro et al .(8) 99 + + + (n=35)

+ +

(GHRH- GHRP6; GST n=44)

GHRH- GHRP6: peak GH ≤ 10 µg/L GST and IT T : GH 3 µg/L

IGF-I < 200 µg/L (±2SDS) IRM A/ IRM A* 10 S chneider et al .(11) 70 + + – +

(n=32)

– GH < 9.0 µg/L A ge -dependen t SDS

CLA/CLA 10 Tanr iv er di et al .(12) 52 + + – – + (GHRH- GHRP6; n=52) GH < 10 µg/L IGF-I < 84 µg/L IRM A/ IRM A* 33

T a b le 2 . C o n ti n u e d

57

S tudy

N o . of pa tien ts

B asal ser um GH

B asal ser um IGF-I IT T

GHRH- ar ginine test

O ther dynamic test

C rit erion GH defi cienc y A ssa y s GH / IGF-I O ut come (%) GH IGF -I Her rmann et al .(5) 76 + + + (n=7)

+ (n=76)

– GHRH-ar g: GH < 9 µg/L IT T : GH peak <3 µg/L 16–24 yr : 182–780 µg/L 25–39yr : 114–492 µg/L 40–54 yr : 90–360 µg/L ≥ 55 yr : 71–290 µg/L

CLA/IRM A 8 Bushnik et al .(4) 64 + + – – + (GST ; n=59)

S ev er e GHD = peak GH < 3 µg/L M oder a te: peak GH 3 –9.9 µg/L

IGF-I age -c or rec ted nor mal lev els NR P ar tial: 66 S ev er e: 39 K lose et al . (7) 104

+ + + (n=90)

+ (n=14)

– S ev er e GHD = IT T : peak GH< 3 µg/L GHRH-ar g: GH< 9 μg/L P ar tial GHD: = IT T : peak GH 5 μg/L ≤ GH ≥ 3 μg/L GHRH-ar g: peak 16.5 μg/L ≤ GH ≥ 9 μg/L

IGF-I SDS

FIA/RIA 15 Tanr iv er di et al .(14) 30 + + – – + (GRHR- GHRP6 n=30; GST n=7)

GRHR- GHRP6: sev er e GHD = GH < 10 µg/L GST : GH < 1.18 µg/L 18–30 yr : 197–476 µg/L 31–40 yr : 100–494 µg/L 41–70 yr : 101–303 µg/L

IRM A/ IRM A* 23

58

S tudy

N o . of pa tien ts

B asal ser um GH

B asal ser um IGF-I IT T

GHRH- ar ginine test

O ther dynamic test

C rit erion GH defi cienc y A ssa y s GH / IGF-I

O ut come (%) GH IGF -I W ach ter et al .(13) 55 + + – – + (GHRH; n=NR)

NR A ge adjust ed: 116–270 μg/L NR 2 A C S , Au to m a te d ch e m il u m in e sc e n ce sy st e m ; A U C , a re a u n d e r th e cu rv e ; C L , c o n fi d e n ce li m it ; C L A , c h e m il u m in o m e tr ic a ss a y ; F IA , fl u o ro im m u n o a ss a y ; G H D , g ro w th h o rm o n e d e fi ci e n c y ; G H I, g ro w th h o rm o n e in su ffi c ie n c y ; G R H R , g ro w th h o rm o n e re le a si n g h o rm o n e ; G H R H -G H R P 6 te st , g ro w th h o rm o n e re le a si n g h o rm o n e p lu s g ro w th h o rm o n e re le a si n g p e p ti d e 6 ; G S T, g lu ca g o n st im u la ti o n te st ; I G F -I , i n su li n -l ik e g ro w th fa c to r I; IR M A , i m m u n o ra d io m e tr ic a ss a y ; I T T, in su li n t o le ra n ce t e st ; N R , n o t r e p o rt e d ; R IA , r a d io i m m u n o m e tr ic a ss a y

N o rm a l v a lu e s d e fi n e d b y a g ro u p o f h e a lt h y s u b je c ts ( n = 1 8 )

¾ p a ti e n ts w it h G H D h a d b e e n t e st e d < 1 2 m o n th s p o st T B I ( 7, 5 ,5 m o n th s)

G S T i n n = 4 8 ; n = 2 0 u n d e rw e n t L -d o p a t e st

C u t- o ff v a lu e s d e fi n e d b y 3 1 h e a lt h y c o n tr o l s u b je c ts

A ll p a ti e n ts u n d e rw e n t G S T; p a ti e n ts w it h a b n o rm a l r e su lt s u n d e rw e n t I T T ( n = 1 4 ) o r G H R H + a rg t e st ( n = 4 )

P a ti e n ts w it h I G F -I i n l o w e r r a n g e w e re t e st e d w it h G H R H -G H R P 6 ( n = 4 4 ,g lu ca g o n s ti m u la ti o n t e st ( n = 4 4 ) a n d I T T ( n = 3 5 )

3 8 h e a lt h y c o n tr o ls u n d e rw e n t G H R H -a rg t e st t o t e st a p p ro p ri a tn e ss o f c u t- o ff v a lu e s

C a lc u la te d a cc o rd in g t o B ra b a n t et a l.2 0 0 3 (3 1)

G S T: 0 .0 3 m g k g -1 m a x 1 m g i n tr a m u sc u la r

3 0 a g e - a n d B M I- m a tc h e d h e a lt h y c o n tr o ls a ll u n d e rw e n t p it u it a ry t e st in g

C a lc u la te d b y J u u l e t a l. 1 9 9 4 (3 2 )

P a ti e n ts w it h u n ce rt a in l e v e ls o f G H a ft e r G H R H -G R H P 6 ( G H 1 1 –1 9 µ g /L ) t e st u n d e rw e n t G S T ( n = 7 )

H o rm o n a l st im u la ti o n te st s w e re p e rf o rm e d if a b n o rm a li ti e s in b a sa l h o rm o n e sc re e n in g o r if p a ti e n ts a n sw e re d ‘y e s’ to sp e ci fi c q u e st io n n a ir e . N o t re p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t s ti m u la ti o n t e st s. G H R H : 1 0 0 μ g * A ft e r a ci d -e th a n o l e x tr a c ti o n

T a b le 2 . C o n ti n u e d

59

T a b le 3 . H y p o th a la m ic -P it u it a ry A d re n a l A x is S tudy

N o . of pa tien ts

B asal ser um cor tisol

B asal ser um A C TH CRH t est

A C TH test IT T

O ther dynamic test

C rit erion f or A C TH- defi cienc y

A ssa y cor tisol/ A C TH

O ut come (%) Kelly et al . (6) 22 + + – – + (n=22)

– C or tisol < 95% CI ac cor ding to A UC

RIA/IRM A 5 Lieber man et al . (9) 70 + – – + (n=70)

– – P eak c or tisol < 500 nmol/L MSA/- 7 B ondanelli et al . (3) 50 + + – – – – C or tisol and A C TH belo w repor ted r ef er enc e r ange (c or tisol: 220 – 700 nmol/L A C TH: 1.5–11.5 pmol/L)

RIA/IRM A 0 A gha et al . (1) 102

+ + – + (n=8)

+ (n=15)

+ (GST ; n=102)

Failing 2 t ests: GST : peak c or tisol < 450 nmol/L IT T : peak c or tisol < 500 nmol/L SST : peak c or tisol <500 nmol/L

FIA/IRM A 13 P opo vic et al .(10) 67 + – – – – – NR RIA/- 7 A imar etti et al .(2) 70 + – – – – – C or tisol < 220 nmol/L 24h ur inar y fr ee c or tisol < 30 µg/24 h

RIA/- 9

60

S tudy

N o . of pa tien ts

B asal ser um cor tisol

B asal ser um A C TH

CRH test

A C TH test IT T

O ther dynamic test

C rit erion f or A C TH– defi cienc y

A ssa y cor tisol/ A C TH

O ut come (%) Leal- C er ro et al .(8) 99 + + – – +

(n=NR)

– Basal c or tisol < 200 nmol/L P eak c or tisol < 550 nmol/L P eak A C TH < 6.6 pmol/L

FIA / IRM A 11 S chneider et al .(11) 70 + – – + (n=33)

– – C or tisol < 500 nmol/L ECLIA/- 9 Tanr iv er di et al .(12) 52 + + – + (n=12)

– – Basal c or tisol < 193 nmol/L A C TH t est: C or tisol < 552 nmol/L

RIA/IRM A 19 Her rmann et al .(5) 76 + + – – + (n=7)

– C or tisol and A C TH belo w repor ted r ef er enc e r ange (c or tisol 180–640 nmol/L; A C TH 3.74– 11.44 pmol/L) IT T : P eak c or tisol < 500 nmol/L

IA/CL 3 Bushnik et al .(4) 64 + – – – – – Fasting serum c or tisol < 440 nmol/L NR 60 K lose et al . (7) 104

+ + – + (n=14)

+ (n=90)

– P eak c or tisol < 500 nmol/L ECLIA /- 5 Tanr iv er di et al .(14) 30 + + – + (n=3)

– – Basal c or tisol < 193 nmol/L A C TH t est: C or tisol < 550 nmol/L

RIA/IRM A 7

T a b le 3 . C o n ti n u e d

61

S tudy

N o . of pa tien ts

B asal ser um cor tisol

B asal ser um A C TH

CRH test

A C TH test IT T

O ther dynamic test

C rit erion f or A C TH– defi cienc y

A ssa y cor tisol/ A C TH

O ut come (%) W ach ter et al .(13) 55 + + + (n=NR)

– – – C or tisol belo w r epor ted ref er enc e r ange (c or tisol (16:00 – 20:00 h): 63 – 339 nmol/L)

NR 4 A C S , Au to m a te d ch e m il u m in e sc e n ce sy st e m ; A C T H , a d re n a l c o rt ic o tr o p e h o rm o n e ; A U C , a re a u n d e r th e cu rv e ; C L , c o n fi d e n ce li m it ; C L A , c h e m il u m in o m e tr ic a ss a y ; C R H , co rt ic o tr o p e re le a si n g h o rm o n e ; E C L IA , e le c tr o ch e m il u m in is ce n ce im m u n o a ss a y ; F IA , fl u o ro im m u n o a ss a y ; G S T, g lu ca g o n st im u la ti o n te st ; IA , Im m u n o a ss a y ; I R M A , i m m u n o ra d io m e tr ic a ss a y ; I T T, in su li n to le ra n ce te st ; M E IA , m ic ro p a rt ic le e n zy m e im m u n o a ss a y ; M S A , m a g n e ti c se p a ra ti o n a ss a y s; N R , n o t r e p o rt e d ; R IA , r a d io i m m u n o m e tr ic a ss a y ; S S T, s h o rt s y n a c th e n s ti m u la ti o n t e st

N o rm a l v a lu e s d e fi n e d b y a g ro u p o f h e a lt h y s u b je c ts ( n = 1 8 )

A C T H t e st : 2 5 0 μ g c o sy n tr o p in

C u t- o ff v a lu e s d e fi n e d b y 3 1 h e a lt h y c o n tr o l s u b je c ts

A C T H t e st : 2 5 0 μ g S y n a c th e n

P a ti e n ts w it h s u b n o rm a l r e sp o n se t o G S T ( n = 2 3 ) u n d e rw e n t I T T ( n = 15 ) o r S S T ( n = 8 )

P a ti e n ts w it h s u b n o rm a l b a sa l s e ru m c o rt is o l a n d A C T H v a lu e s u n d e rw e n t I T T; n o t r e p o rt e d h o w m a n y p a ti e n ts c o rt is o l < 2 0 0 n m o l/ L

A C T H t e st : 2 5 0 μ g S y n a c th e n

A C T H t e st : 1 μ g S y n a c th e n

P a ti e n ts w it h s u b n o rm a l b a sa l s e ru m c o rt is o l a n d A C T H v a lu e s u n d e rw e n t I T T ( n = 7 )

3 0 a g e - a n d B M I- m a tc h e d h e a lt h y c o n tr o ls a ll u n d e rw e n t p it u it a ry t e st in g

A C T H t e st : 2 5 0 μ g S y n a c th e n

A C T H t e st : 1 μ g S y n a c th e n

H o rm o n a l st im u la ti o n te st s w e re p e rf o rm e d if a b n o rm a li ti e s in b a sa l h o rm o n e sc re e n in g o r if p a ti e n ts a n sw e re d ‘y e s’ to sp e ci fi c q u e st io n n a ir e . N o t re p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t s ti m u la ti o n t e st s; C R H t e st : 1 0 0 μ g c o rt ic o tr o p e r e le a si n g h o rm o n e

62

T a b le 4 . H y p o th a la m u s P it u it a ry T h y ro id A x is S tudy

N o . of pa tien ts

B asal ser um fT

B asal ser um fT

B asal ser um T SH TRH C rit erion TH defi cienc y

A ssa y T SH/FT

O ut come (%) Kelly et al .(6) 22 – + + + (n=22)

T SH < 95% CL ac cor ding t o A UC

ICL/ RIA 5 Lieber man et al .(9) 70 – + + + (n=27)

T SH: 0.49–4.7 mIU/L fT

: 9.7 – 23.8 pmol/L Insuffi cien t ↑ T SH (5–30 mIU/L); peak T SH not within 60 min

MPIA/ MPIA 15 B ondanelli et al .(3) 50 – + + – Lo w serum fT

with nor mal or lo w serum T SH T SH: 0.4–4.2 mIU/L fT

: 10.3–19.4 pmol/L

A CS/A CS 10 A gha et al .(1) 102

– + + – Lo w fT

without elev a tion T SH T SH: 0.5 –4.2 mIU/L fT

: 8–21 pmol/L

FIA/FIA 1 P opo vic et al . (10) 67 – + + – NR IRM A/RIA 4 A imar etti et al . (2) 70 – + + – fT

< 10.29 pmol/L with nor mal or lo w T SH IRM A/RIA 6 Leal- C er ro et al .(8) 99 – + + + (n=NR)

fT

≤ 7.74 pmol/L with nor mal or lo w T SH TRH t est: T SH peak ≤ 7 mIU/L RIA/RIA 6

63

S tudy

N o . of pa tien ts

B asal ser um fT

B asal ser um fT

B asal ser um T SH TRH C rit erion TH defi cienc y

A ssa y T SH/FT4

O ut come (%) S chneider et al .(11) 70 – + + – fT

< 11.97 pmol/L; T SH not elev a ted ECLIA/ ECLIA 4 Tanr iv er di et al .(12) 52 + + + + (n=NR)

fT

< 10.3 pmol/L without appr opr ia te elev a tion T SH fT

, fT

: RIA T SH: IRM A 6 Her rmann et al .(5) 76 + + + – Lo w serum fT

without appr opr ia te elev a tion in serum T SH T SH: 0.3–3.0 mIU/L fT

: 10–25 pmol/L

IA/IA 3 Bushnik et al . (4) 64 – + + – Lo w serum fT

with lo w or nor mal T SH Nor mal r ef er enc e v alues: NR NR 19 K lose et al .(7) 104

– + + – Subnor mal fT

(<12 pmol/L) with inappr opr ia te lo w T SH ECLIA/ ECLIA 2 Tanr iv er di et al .(14) 30 + + + – fT

< 10.3 pmol/L without appr opr ia te elev a tion T SH fT

, fT

: RIA T SH: IRM A 0

64

S tudy

N o . of pa tien ts

B asal ser um fT

B asal ser um fT

B asal ser um T SH TRH C rit erion TH defi cienc y

A ssa y T SH/FT4

O ut come (%) W ach ter et al . (13) 55 – + + + (n=NR)

C rit er ion f or TRH t est: NR fT

: 12–22 pmol/L T SH: NR

NR 6 A C S , Au to m a te d ch e m il u m in e sc e n ce sy st e m ; A U C , a re a u n d e r th e cu rv e ; C L , co n fi d e n ce li m it ; E C L , E le c tr o ch e m il u m in is ce n ce im m u n o a ss a y ; F IA , F lu o ro im m u n o a ss a y ; f T

: f re e tr ii o d o th y ro n in e ; f T

, f re e th y ro x in e ; I R M A , i m m u n o ra d io m e tr ic a ss a y ; I C L , I m m u n o ch e m o lu m in is ce n se ; M PI A , m ic ro p a rt ic le e n zy m e i m m u n o a ss a y ; N R , n o t r e p o rt e d ; R IA , r a d io i m m u n o a ss a y ; T R H , t h y ro id r e le a si n g h o rm o n e ; T S H , t h y ro id s ti m u la ti n g h o rm o n e

T R H t e st : 5 0 0 µ g

N o rm a l v a lu e s d e fi n e d b y a g ro u p o f h e a lt h y s u b je c ts ( n = 1 8 )

A b n o rm a l T S H a n d f T

v a lu e s u n d e rw e n t T R H s ti m u la ti o n t e st ( n = 2 7 ); 0 .5 m g T R H ; I V , T S H a t T 0 , 1 5 , 3 0 , 6 0 , 9 0 m in

C u t- o ff v a lu e s d e fi n e d b y 3 1 h e a lt h y c o n tr o l s u b je c ts

T R H t e st : 5 0 0 µ g P ro ti re li n

N o t r e p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t T R H t e st in g a n d h o w t h e t e st w a s p e rf o rm e d

3 0 a g e - a n d B M I- m a tc h e d h e a lt h y c o n tr o ls a ll u n d e rw e n t p it u it a ry t e st in g

H o rm o n a l st im u la ti o n te st s w e re p e rf o rm e d if a b n o rm a tl it ie s in b a sa l h o rm o n e sc re e n in g o r if p a ti e n ts a n sw e re d ‘y e s’ to sp e ci fi c q u e st io n n a ir e . N o t re p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t s ti m a lt io n st s. T R H : 2 0 0 μ g

T a b le 4 . C o n ti n u e d

65

T a b le 5 . H y p o th a la m u s p it u it a ry g o n a d a l A x is S tudy

N o . of pa tien ts

B asal ser um LH

B asal ser um FSH

B asal ser um E

/T

M enstr ual hist or y G nRH S timula- tion t est C rit erion f or h yp o gonadism A ssa y LH/FSH/T/E

O ut- come (%) Kelly et al . (6) 22 + + + + + (n=18)

LH and FSH < 95% CL ac cor ding t o A UC

F : incr ease LH <10 IU/L af ter GnRH administr a tion T : 10.3 – 36.2 nmol/L E

: (ear ly f ollicular phase) 73.4–550.7 pmol/L LH, FSH: FIA T : RIA E

: dir ec t assa y

23 Lieber man et al .(9)

70 + – T+ + +

(n=NR)

T belo w r epor ted r ef er enc e r ange ( 9.7 – 30.5 nmol/L) LH belo w r epor ted r ef er enc e r age (M= 2–12 IU/L) Nor mal r esponse GnRH t est: M: peak LH <12 IU/L and incr ease in LH < 7 IU/L F : peak LH < 10 IU/L and incr ease in LH < 5 IU/L T : RIA LH: MEIA

0

66

S tudy

N o . of pa tien ts

B asal ser um LH

B asal ser um FSH

B asal ser um E

/T

M enstr ual hist or y G nRH S timula- tion t est C rit erion f or h yp o gonadism A ssa y LH/FSH/T/E

O ut- come (%) B ondanelli et al .(3)

50 + + + NR – LH belo w r epor ted r ef er enc e r ange: F : f ollicular phase 2.5–10 IU/L; menopausal 40–104 IU/L M: 1–10 IU/L FSH belo w r epor ted r ef er enc e r ange: F : f ollicular phase 2.5–10 IU/L; menopausal 34–96 IU/L M: 1–7 IU/L T belo w r epor ted r ef er enc e r ange (10.1–34.7 nmol/L) E

belo w r epor ted r ef er enc e r ange (f ollicular phase 74–555 pmol/L; menopausal <180pmol/L) LH, FSH: CLIA T, E

: RIA

14 A gha et al .(1) 102

+ + T+ + – M: lo w T ; inappr opr ia tely lo w LH and FSH P remenopausal F : amenor rhea with lo w E

without ↑ LH and FSH P ostmenopausal F : LH and FSH in r ange of pr emenopausal

LH, FSH: FIA 12 P opo vic et al . (10)

67 + + T+ + – NR LH, FSH: IRM A T : RIA

9 A imar etti et al .(2)

70 + + + + – M : T < 12.1 nmol/L with lo w or nor mal FSH and LH P remenopausal F : menstrual distur banc es , lo w E

< 73.4 pmol/L with nor mal or lo w LH and FSH LH, FSH: IRM A T,E

: RIA

11

T a b le 5 . C o n ti n u e d

67

S tudy

N o . of pa tien ts

B asal ser um LH

B asal ser um FSH

B asal ser um E

/T

M enstr ual hist or y G nRH S timula- tion t est C rit erion f or h yp o gonadism A ssa y LH/FSH/T/E

O ut- come (%) Leal- C er ro et al .(8)

99 + + + + + (n=NR)

M: T < r ef v al with nor mal LH and FSH F : menstrual disor der or amenor rhea af ter TBI, E

<0.08 nmol/L nor mal or lo w LH and FSH T : RIA E

, LH, FSH: FIA

29 S chneider et al .(11)

70 + + + + – M: T < 12.1 nmol/ without ↑ LH and FSH P remenopausal F = no menses P ostmenopausal F = lo w FSH, LH

A ll: ECL 29 Tanr iv er di et al .(12)

52 + + + NR – M: T < r ef er enc e v alues; nor mal or ↓ LH and FSH P remenopausal F : E

< 40.4 pmol/L; inappr opr ia te lo w LH and FSH P ostmenopausal F : LH and FSH in r age of pr emenopausal w omen T : RIA E

: CLIA LH, FSH: RIA

8 Her rmann et al .(5)

76 + + + + – M: ↓ T ; inappr opr ia tely lo w LH and FSH P remenopausal F : amenor rhea ↓ E

without ↑ LH and FSH P ostmenopausal F : LH and FSH in pr emenopausal r ange

A ll: IA 17 Bushnik et al . (4)

64 – – T+ – – M: t est ost er one defi cienc y : T < 9.0 nmol/L NR 17 K lose et al .(7) 104

+ + +

+ – M: T < 10 nmol/L; inappr opr ia te lo w LH; inhibin B and SHBG P remenopausal F : amenor rhoea/ oligomenor rhoe; lo w E

, LH,FSH P ostmenopausal F : inappr opr ia te lo w LH,FSH for age

A ll: ECL 2

68

S tudy

N o . of pa tien ts

B asal ser um LH

B asal ser um FSH

B asal ser um E

/T

M enstr ual hist or y G nRH S timula- tion t est C rit erion f or h yp o gonadism

A ssa y LH/FSH/T/E

O ut- come (%) Tanr iv er di et al .(14)

30 + + + + – M: T < nor mal (t otal T < 4.6 nmol/L; fr ee T < 11.5pg/ml); nor mal or ↓ LH, FSH P remenopausal F : E

< 40.4 pmol/L; inappr opr ia te lo w LH, FSH P ostmenopausal F : LH, FSH in r age of pr emenopausal w omen T : RIA E

: CLIA LH, FSH: RIA

0 W ach ter et al .(13)

55 + + T+ – + (n=NR)

T belo w r epor ted r ef er enc e r ange (9.7– 27.7 nmol/L) E

belo w r epor ted r ef er enc e r ange: (f ollicular phase 48–709 pmol/L; midc ycle peak 316–1828 pmol/L; lut eal phase 162–775 pmol/L; postmenopausal < 128 pmol/L) A bnor mal r esponse LHRH t est: NR

NR 13 A C S , a u to m a te d ch e m il u m in e sc e n ce sy st e m ; A U C , a re a u n d e r th e cu rv e ; C L , c o n fi d e n ce li m it ; C L IA , c h e m il u m in o m e tr ic im m u n o a ss a y ; E

e st ra d io l; E C L , e le c tr o ch e m il u m in is ce n ce ; F, fe m a le ; F IA , fl u o ro im m u n o a ss a y ; F S H , fo ll ic le st im u la ti n g h o rm o n e ; G H D , g ro w th h o rm o n e d e fi ci e n c y ; G n R H , g o n a d o tr o p e re le a si n g h o rm o n e ; IA , Im m u n o a ss a y ; IR M A , im m u n o ra d io m e tr ic a ss a y ; L H , l u te in iz in g h o rm o n e ; L H R H , l u te in iz in g h o rm o n e re le a si n g h o rm o n e ; M , m a le ; M E IA , m ic ro p a rt ic le e n z y m e im m u n o a ss a y ; M S A , m a g n e ti c se p a ra ti o n a ss a y s; N R , n o t r e p o rt e d ; R IA , r a d io i m m u n o m e tr ic a ss a y ; T , t e st o st e ro n e

N o rm a l v a lu e s d e fi n e d b y a g ro u p o f h e a lt h y s u b je c ts ( n = 1 8)

P a ti e n ts w it h a b n o rm a li ti e s i n b a sa l t e st o st e ro n e l e v e ls o r m e n st ru a l h is to ry u n d e rw e n t G n R H ; o n ly L H m e a su re m e n ts

C u t- o ff v a lu e s d e fi n e d b y 3 1 h e a lt h y c o n tr o l s u b je c ts

3 0 a g e - a n d B M I- m a tc h e d h e a lt h y c o n tr o ls a ll u n d e rw e n t p it u it a ry t e st in g

In c a se o f s u sp e c te d h y p o g o n a d is m i n m e n , e v a lu a ti o n w a s r e p e a te d w it h m e a su re m e n t o f i n h ib in B a n d S H B G

H o rm o n a l st im u la ti o n te st s w e re p e rf o rm e d if a b n o rm a tl it ie s in b a sa l h o rm o n e sc re e n in g o r if p a ti e n ts a n sw e re d ‘y e s’ to sp e ci fi c q u e st io n n a ir e . N o t re p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t s ti m a lt io n s t e st s; L H R H : 1 0 0 μ g

T a b le 5 . C o n ti n u e d

69

T a b le 6 . P ro la c ti n s e cr e ti o n S tudy

N o . of pa tien ts

B asal ser um PRL TRH C rit erion f or abnormal PRL secr etion

A ssa y PRL

O ut come (%) Kelly et al . (6) 22 – + (n= NR)

H ypopr olac tinemia: PRL < 95% CL ac cor ding t o A UC

RIA 0 Lieber man et al .(9) 70 + – H yper pr olac tinemia: M: > 565 pmol/L F : > 1160 pmol/L

MSA 0 B ondanelli et al .(3) 50 + – H yper pr olac tinemie = PRL abo v e r epor ted r ef er enc e r ange H ypopr olac tinemia = PRL belo w r epor ted r ef er enc e r ange (M: 87 – 696 pmol/L; F : 174 – 1043 pmol/L)

A CS 16 A gha et al . (1) 102

+ – H yper pr olac tinemia = basal lev el PRL > than the locally der iv ed nor mal assa y r ef er enc e r ange (M: 83–414 mIU/L; F : 90–523 mIU/L ) FIA 12 P opo vic et al .(10) 67 + – NR IRM A 12 A imar etti et al .(2) 70 + – H yper pr olac tinemia: NR IRM A 6 Leal- C er ro et al .(8) 99 + +

(n=NR)

NR NR NR S chneider et al .(11) 70 + – H yper pr olac tinemia: PRL > 1087 pmol ECLIA NR

70

S tudy

N o . of pa tien ts

B asal ser um PRL TRH C rit erion f or abnormal PRL secr etion

A ssa y PRL

O ut come (%) Tanr iv er di et al .(12) 52 + – H yper pr olac tinemia: basal lev el g rea ter than the nor mal r ef er enc e range (M: 87 –1783 pmol; pr emenopausal F : 122–1261 pmol; postmenopausal F :78–870 pmol)

RIA 8 Her rmann et al .(5) 76 + – H yper pr olac tinemia: PRL abo v e r epor ted r ef er enc e r ange (M:870 pmol; F : <1087 pmol) IA 3 Bushnik et al .(4) 64 – – – – – K lose et al . (7) 104

+ – H yper pr olac tinemia: PRL > 510 mIU/L ECLIA NR Tanr iv er di et al .(14) 30 + – H yper pr olac tinemia: basal lev el g rea ter than the nor mal r ef er enc e range (M: 87 –1783 pmol; pr emenopausal F : 122–1261 pmol; postmenopausal F : 1.8–20 ng/ml)

RIA NR W ach ter et al .(13) 55 + +

(n=NR)

NR NR NR A U C , a re a u n d e r th e cu rv e ; A C S , a u to m a te d ch e m il u m in e sc e n ce sy st e m ; C L , co n fi d e n ce li m it ; E C L IA , E le c tr o ch e m il u m in is ce n ce im m u n o a ss a y ; F IA , F lu o ro im m u n o a ss a y ; I A , I m m u n o a ss a y ; IR M A , i m m u n o ra d io m e tr ic a ss a y ; M S A , m a g n e ti c se p a ra ti o n a ss a y s; N R , n o t re p o rt e d ; P R L , p ro la c ti n ; R IA , r a d io im m u n o m e tr ic a ss a y ; T R H , t h y ro id re le a si n g h o rm o n e

N o rm a l v a lu e s d e fi n e d b y a g ro u p o f h e a lt h y s u b je c ts ( n = 1 8 )

C u t- o ff v a lu e s d e fi n e d b y 3 1 h e a lt h y c o n tr o l s u b je c ts

T R H t e st : 5 0 0 u g

3 0 a g e - a n d B M I- m a tc h e d h e a lt h y c o n tr o ls a ll u n d e rw e n t p it u it a ry t e st in g

H o rm o n a l st im u la ti o n te st s w e re p e rf o rm e d if a b n o rm a li ti e s in b a sa l h o rm o n e sc re e n in g o r if p a ti e n ts a n sw e re d ‘y e s’ to sp e ci fi c q u e st io n n a ir e . N o t re p o rt e d h o w m a n y p a ti e n ts u n d e rw e n t s ti m u la ti o n t e st s. T R H : 1 0 0 μ g

T a b le 6 . C o n ti n u e d

71

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